Conclusions

Normothermia is usual within the first 4 hours of stroke. Peak temperature occurs at 1.5 to 2 days after stroke, and is related to stroke severity/subtype and more closely associated with poor outcome than admission temperature. Temperature-outcome associations after stroke are complex, but normothermia on admission should not preclude randomisation of patients into trials of therapeutic hypothermia.

Keywords

Ischemic strokeTympanic body temperaturePyrexiaOutcomeOCSP

Background

Elevated body temperature (pyrexia) is said to be common after stroke [1, 2] and is associated with poor outcome [2–10]. However, the timing of pyrexia after stroke varied between studies (Table 1). Pyrexia occurring early might reflect the systemic response to ischemic brain damage [11] whereas pyrexia occurring later might be due to complications of severe stroke, such as infection and deep venous thrombosis (DVT). However data on timing, causes and associations between body temperature and outcome vary.

Amongst the 18 previous studies of temperature after stroke (Tables 1 and 2), four performed only one temperature recording [3, 6, 12, 20], some measured temperature at admission but relatively late (e.g. 24 hours) [11] or at unspecified times after stroke [2, 4, 7]. Where serial readings were obtained, this was only up to three days after stroke [8, 9, 13, 15, 18, 22]. Six studies included haemorrhagic and ischemic stroke [2–4, 6, 12, 19]. Definitions of pyrexia, temperature measurement methods, reporting of associations with stroke severity and of causes of pyrexia varied widely [2, 7, 10, 14, 16, 17, 21]. Thus, while some studies found associations between higher admission temperature and poor outcome (Table 2) [3, 6, 12], others found that peak temperature occurring several days after stroke, not admission temperature, was associated with poor outcome [7, 16, 17, 19]. The reasons for these differences are unclear but important to understand to limit brain damage and improve outcome after stroke.

We obtained measurements of body temperature every four hours from admission to five days after acute ischemic stroke as part of a study to examine serial changes in the ischaemic lesion on MR imaging. We used these data to clarify the temporal profile, associations with stroke severity, subtype and functional outcome and proportion with an alternative explanation for pyrexia.

Methods

We prospectively recruited patients >18 years old who presented with potentially disabling ischemic stroke. We excluded patients with intracerebral haemorrhage (ICH), coma, serious intercurrent illness, and technical or clinical incompatibility with MR scanning. Ethical approval was granted by the Scottish Multi-Centre Research Ethics Committee (06/MRE00/119) and we obtained informed, written consent from all patients or their relatives.

At admission, we recorded National Institute of Health Stroke Score (NIHSS) and the Oxford Community Stroke Project (OCSP) stroke subtype classification [23]. All patients underwent MR imaging to diagnose the ischemic stroke. We recorded temperature using a First Temp Genius® tympanic thermometer immediately on arrival at hospital, and four hourly thereafter up to 120 hours. Recordings were taken from the uppermost ear in most patients, and from both ears in 11 patients to test side-to-side variation [24]. Tympanic thermometry is considered reliable for serial readings [25], shows the least variation with age compared with axillary, rectal and oral thermometry [26], and is widely used in clinical practice. Pyrexia was defined as temperature ≥37.5°C [10]. We searched for causes of pyrexia by collecting data on evidence of infection (evident infectious agent, leukocytes in body fluid, signs on imaging), DVT and surgical intervention as well as paracetamol and antibiotic use. Our policy is to prescribe paracetamol to patients who develop pyrexia (or for other indications such as pain relief) and antibiotics when positive evidence of infection and an infectious agent is diagnosed. We recorded modified Rankin Scale score (mRS) at three months after stroke, blind to temperature measurements.

We compared admission, peak and final temperatures and calculated area under the temperature/time curve (AUC)[27] which we standardised (AUC[s]) by assuming all patients had a temperature of 36.5°C between stroke and the admission recording, and dividing AUC by the time of final temperature reading [27]. We tested the association between temperature profile and measures of stroke severity firstly as determined by NIHSS, secondly by comparing total anterior circulation strokes (TACS) vs. less severe stroke subtypes (non-TACS) and thirdly good (mRS ≤2) vs. poor (mRS≥3) 90 day outcome. We adjusted analysis for age and admission NIHSS where appropriate. We used Student’s t-test for parametric and Mann Whitney U tests and Spearman correlation for non-parametric data.

Results

Between 7th December 2007 and 24th March 2009, we recruited 48 patients but excluded two with ICH, one with complex migraine and one with functional limb weakness, leaving 44 with acute ischemic stroke (21 males) of median age 74 years (range 37–88) and median admission NIHSS 7 (range 0–28). There were 14 TACS and 30 non-TACS (Table 3). Twenty-five patients had poor (mRS≥3) and 19 had good (mRS≤2) 90 day functional outcomes. Patients with poor outcome were older (75±10) with higher admission NIHSS (13±7) than patients with good outcome (68±11 and 5±4 respectively).

Table 3

Baseline data, pyrogenic factors and use of antibiotics and thrombolysis

There was no difference between ipsi- and contralateral tympanic temperature readings obtained simultaneously (36.6°C vs 36.6°C, 95% confidence interval (CI) -0.19 to 0.16, p=0.821) in 11 patients (five TACS). The mean number of temperature readings per patient was 14 (SD 6.9). No patients died during the observation period.

Sixteen (36%) patients became pyrexial (at least one temperature reading of ≥37.5°C) during the recording period: 9/14 (64%) TACS patients and 7/30 (23%) non-TACS (χ2=6.9, p=0.009). Of the 16 pyrexial patients, at least one potential cause of pyrexia was identified in nine (56%), but 11/16 (69%) had no infection and 7/16 (44%) had no identified cause for pyrexia (apart from the stroke). Conversely, a potential pyrogenic factor was identified in 7/28 (25%) patients without pyrexia (Table 3). Thirteen patients were prescribed paracetamol of whom seven were recorded as having pyrexia and six were not (OR for pyrexia associated with paracetamol=1.8, 95% CI 0.48 to 6.77). The reason for paracetamol administration in the patients without pyrexia was mostly for pain relief. Ten patients with poor outcome (40%) had been prescribed paracetamol but only in three (16%) patients with good outcome (OR for poor outcome 3.56, 95% CI 0.82 to 15.46).

Discussion

In patients with ischemic stroke, tympanic temperature was not elevated on admission even in patients with more severe strokes (TACS), and admission temperature did not correlate with admission NIHSS. Instead, we found that peak temperature, occurring at around 1.5 to 2 days after stroke and overall temperature, as expressed by AUC were associated with admission stroke severity as measured by NIHSS and TACS subtype. Peak temperatures were higher, occurred later and temperature elevation lasted longer in more severe than less severe strokes perhaps indicating a more prolonged, greater inflammatory response to the volume of infarcted tissue. Patients with poor functional outcome (mRS≥3) at 90 days had higher admission and peak temperatures than patients with good outcome (mRS≤2), although all admission temperatures were <37°C. We were not able to find a source of infection in 69% of pyrexial patients, and no alternative cause of pyrexia, other than the stroke itself, in 44%.

This prospective study of detailed four-hourly tympanic temperature measurements up to five days after ischemic stroke helps explain the varying results of previous studies (Tables 1 and 2) some of which found associations between admission temperature, stroke severity and outcome [3, 4, 6, 12, 13], while others did not [8, 14, 16, 19]. This variation can be attributed to some studies being retrospective, or not specifying the timing of temperature recording after stroke, sampling temperature only once, measuring “admission” temperature relatively late after stroke, only measuring serial temperature up to 72 hours, the different severities of stroke included in each study or including patients with both haemorrhagic and ischemic stroke. Consistent with our results, others showed that patients with more severe strokes experience higher peak temperatures [15], and that elevated temperature at 24 hours [14, 17, 19], 48 hours [8] or 7 days [7] after stroke was more closely linked to poor outcome than admission readings. Our detailed longitudinal findings also demonstrate the higher, later and longer duration of temperature elevation in more severe than less severe stroke, which perhaps has not been appreciated previously.

Our study has limitations. The small sample size was constrained by selection of patients for an MR imaging study, but on the other hand it allowed very detailed temperature monitoring. However, the range of stroke severity was consistent with those that would be considered for trials of therapeutic hypothermia. A larger sample size would allow more adjustment for potential confounders, and clarification of the significance of any differences in timing of peak temperature readings, and comparison of patients whose tympanic temperature may have been affected by antibiotics and antipyretics, although our results show that pyrexia was just as common in patients who were prescribed paracetamol as in those who were not, in contrast to others’ results [15]. However paracetamol may have influenced the profile of temperature change. Although our data on temperature profile and stroke severity are consistent with five previous studies, we cannot exclude the possibility of an association between admission temperature and stroke severity. The study strengths are the detailed four-hourly tympanic temperature measurements for 120 hours after ischemic stroke and the detailed comparison with stroke subtype, severity and outcome. The duration of temperature recording ensured that the peak temperature was captured in both TACS and non-TACS.

Two other points raise questions for further study. Admission temperature in the patients with more severe strokes, ie TACS, was not higher than in patients with milder strokes, as might have been expected. Perhaps, by analogy with other serious acute illness, the temperature in severe stroke may reflect severe illness [28]. Secondly, why do patients with a poor outcome have a marginally higher (but still normothermic) admission temperature, and while severe stroke is associated with poor outcome, severe stroke is not associated with admission temperature? This might be explained at least in part by a possible cascade of events suggested in experimental data. Increased temperature opens the blood–brain barrier [29] which, in acute ischemia, would lead to increased extracellular oedema, more infarct swelling, more restricted capillary flow in the ischemic tissue, less chance of reperfusion, all contributing to increasing ischemic damage, swelling and leading to a larger infarct around 48 hours [30], consolidating the potential for tissue damage that was suggested by the severe stroke symptoms at presentation, and consequently leading to the poor outcome at 90 days. Longer duration of temperature monitoring should be considered in future research to improve understanding of temperature profiles after stroke.

This interpretation, if true, raises some implications for therapeutic hypothermia trials. Firstly, and paradoxically, patients may benefit the most from hypothermia if it prevents the tissue cascade outlined above from causing more tissue damage and should certainly not be excluded from trials; thus cooling should be initiated as early as possible and not influenced by the patient’s admission temperature. However cooling may only prevent worsening of damage, not actively salvage tissue that is already at risk, so combinations of therapies to salvage (e.g. thrombolysis) as well as to restrict progressive new damage (e.g. hypothermia, if it works) may be required. Secondly, if the main effect of hypothermia is to reduce blood–brain barrier opening thus preventing the cascade that leads to larger stroke lesions, then hypothermia could still be valuable if started many hours after the stroke when the possibility of salvaging at risk tissue was lost but there was still some “future secondary damage” to prevent. If correct, then hypothermia should reduce subacute infarct oedema and mass effect. Thirdly, if correct, then therapeutic thrombolysis and hypothermia should work synergistically to produce greater benefit than either alone. However hypothermia may also have some disadvantages. In addition to increased risk of secondary infection and the need to manage unpleasant side effects like shivering, lower temperatures might delay thrombus lysis which pyrexia might accelerate. The balance of risk and benefit presented by these possibilities requires testing in future therapeutic trials of hypothermia after stroke.

Conclusion

The association between body temperature, stroke severity and functional outcome is complex and, if our observations in this small detailed study are verified, then even very marginal differences in admission temperature in normothermic patients may provide a mechanism whereby, for a given stroke severity, potential tissue damage is converted into more severe damage resulting in a poor outcome, which might be prevented by therapeutic hypothermia.

Declarations

Acknowledgements

We thank the UK Stroke Research Network nurses who performed the serial temperature measurements. RGT was funded by The Stroke Association (Registered Charity SC037789), Project Ref No: TSA 2006/11, BK by the Foundation for Polish Science and the International Brain Research Organization (IBRO), JMW by the Scottish Funding Council SINAPSE Collaboration (http://www.sinapse.ac.uk).

Competing interests

J Wardlaw is the Imaging Workpackage Lead for the EuroHyp trial of therapeutic hypothermia in stroke. The work was conducted prior to and independently of the EuroHyp trial. The authors have no other competing interests.

Authors’ contributions

RGR Thomas and B Karaszewski recruited patients, collected and entered data in to the database and performed initial analysis. MS Dennis supervised the clinical stroke examination and subtyping. JM Wardlaw initiated and supervised the project, checked the data, and with RG Thomas, drafted and with all authors, edited the manuscript. All authors have read and approved the final manuscript.

Authors’ Affiliations

(1)

Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital

(2)

Department of Adult Neurology, Medical University of Gdansk

(3)

SINAPSE Collaboration, Brain Research Imaging Centre, Division of Clinical Neurosciences, Western General Hospital

Pre-publication history

Copyright

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.